For an active pharmaceutical ingredient which is slightly soluble in water and which rapidly degrades in an acid or base environment, there is a limited number of options as far as pharmaceutical development is concerned. The conventional way to prevent early degradation of the acid or base labile pharmaceutical ingredient is to preserve the ingredient in a micro-pH environment by combining the ingredient with alkaline salts/alkaline compound (i.e., for acid labile pharmaceutical active ingredient) or acid salt/acid compounds (i.e., for base labile pharmaceutical active ingredient).
For example, some of the substituted benzimidazole compounds, as described in U.S. Pat. Nos. 4,255,431 and 4,853,230, have possessed acid labile properties. Such substituted benzimidazoles are a group of compounds which are well known for their pharmacological effects for treating patients with gastrointestinal disorders. These compounds, due to their acid labile characteristics, present a problem for oral formulations, because oral intake of the compounds involves direct contact with acidic gastric juices, which may result in early decomposition of the compounds.
One of these substituted benzimidazole compounds, omeprazole, is especially known for its activity as an inhibitor of H.sup.+ K.sup.+ -ATPase and the proton pump in the gastric mucosa. Omeprazole has the formula of 5-methoxy-2(((4-methoxy-3,5-dimethyl-2-pyridinyl)methyl)sulfinyl)-1H-benzi midazole). Omeprazole can be used for the treatment of gastritis, gastric, peptic, and duodenal ulcers (U.S. Pat. Nos. 4,255,431, 4,786,505, and EPO 124495) as well as Zollinger-Ellison syndrome. In a more general sense, omeprazole may be used for prevention and treatment of other gastrointestinal disorders where cytoprotective and/or gastric antisecretory effect is desirable, e.g., in patients with gastrinomas, in patients with acute upper gastrointestinal bleeding, and in patients with a history of chronic and excessive alcohol consumption.
Omeprazole is very slightly soluble in water, but is very soluble in alkaline solutions in the form of a negatively charged ion. It is an ampholyte with pKa.about.4 (pyridinium) and 8.8 (benzimidazole). Omeprazole degrades very rapidly in water solutions at low pH values. The rate of degradation proceeds with a half-life of less than 10 minutes at pH-values below 4. At pH 6.5 the half-life of degradation is 18 hours; at pH 11 about 300 days. In addition, moisture, organic solvents and acidic substances have a deleterious effect on the stability of omeprazole. (Pilbrant and Cederberg, Scand. J. Gastroenterology (1985) 20:113-120). Because a fully bioavailable dosage form of omeprazole must release the active drug rapidly in the proximal part of the gastrointestinal canal, a conventional oral dosage form since, inter alia, more than half of omeprazole will be degraded before reaching the small intestine.
Various pharmaceutical formulations of omeprazole have been described. For example, U.S. Pat. No. 4,255,431 describes pharmaceutical preparations of omeprazole in tablets and granules dosage forms. The preparations adopt conventional principles by mixing omeprazole with a binding agent to form moistened granules, which then can be compressed into tablets. The pharmaceutical preparations do not contain an enteric coating, which is a conventional way to prevent an acid labile substance from contact with the acidic gastric juice.
Pilbrant and Cederberg, Scand. J. Gastroenterology (1985) 20:113-120, describes an enteric coated dosage form of omeprazole, which, according to their clinical studies, has shown acceptable storage ability. However, such an enteric coated dosage form is unsuitable for long-term storage because the enteric coating is made of acidic compounds. When omeprazole is covered with such an acidic enteric coating, it rapidly decomposes; and the dosage form is badly discolored and decreased in omeprazole content.
U.S. Pat. No. 4,786,505 describes an oral pharmaceutical preparation of omeprazole which contains three distinctive layers: (a) a core which contains omeprazole plus an alkaline reacting compound, an alkaline omeprazole salt plus an alkaline reacting compound, and an alkaline omeprazole salt alone; (b) an inert subcoating which contains tablet excipients and polymeric film-forming compounds; and (c) an enteric coating. This invention differs from U.S. Pat. No. 4,255,431 and Pilbrant and Cederberg's disclosures for its "micro-alkaline pH" core and the inert subcoating which separates the omeprazole core from the enteric coating.
U.S. Pat. No. 5,232,706 describes an oral dosage form of omeprazole which contains (a) a nucleus containing omeprazole or an alkali salt of omeprazole mixed with a basic compound; (b) an intermediate coating formed by an excipient and a basic compound; and (c) an enteric coating. The mixture of compounds of the nucleus can be formulated as pellets, tablets, or gelatin capsule. This invention differs from U.S. Pat. No. 4,786,505 for it contains basic compounds in both the nucleus and the intermediate coating.
The present invention introduces novel pharmaceutical preparations which are suitable for acid or base labile pharmaceutical ingredients. The pharmaceutical preparations are characterized by embedding the acid or base labile pharmaceutical ingredient in an oily matrix, which is preferred to be controlled at neutral pH. The oily matrix-embedded pharmaceutical ingredient is placed into a capsule which is then enteric coated.
In particular, the present invention differs from the prior art omeprazole formulations in the following respects: First, the present invention uses an oily matrix which are controlled at neutral pH as stabilizers to preserve omeprazole. Second, the oily matrix-embedded omeprazole can be in a free base form (i.e., free of alkaline salts or alkaline compounds, or mixed with alkaline or basic compounds) and still afford the same, or better, bioavailability and storage stability as the alkaline form of omeprazole. Third, the present invention uses a capsule as a separation layer to insulate omeprazole from the enteric coating. Fourth, the present invention contains an enteric coating deposited on the capsule. Finally, due to the special effects of the oily matrix, the present pharmaceutical preparation has the advantages over the prior art formulations for its superior resistance to acid media, higher bioavailability, and greater absorption in vivo.